Cross-cell DNA methylation annotation and analysis for pan-cancer study

Pan-cancer study can uncover cell- and tissue-specific genomic loci and regions with underlying biological functions, as one of fundamental procedures toward precision medicine. We utilized the online curated resource of DNA methylation annotation knowledgebase, to implement the cross-cell interrogation of pan-cancer study of breast cancer. The study revealed genome-wide differentially-methylated loci and regions by the reduced representation bisulfite sequencing profiling. The knowledgebase contains three level of curated information across multiple cancer and normal cells from the ENCODE Consortium. The reference base covers all identified differentially-methylation CpG sites and regions of interest, further annotated gene information, together with tumor suppressor gene and methylation level. Lastly, it includes the inferred functional association network and related Gene Ontology analysis results based on all the tumor suppressor genes identified from the differentially-methylated regions of interest. Our knowledgebase and analysis results provide a thorough reference source for biomedical researchers and clinicians. The cross-cell analysis results are deposited at: http://github.com/gladex/DMAK.

Identification of acetyltransferase genes (HAT1 and KAT8) regulating HBV replication by RNAi screening

Background: The initiation of hepatitis B virus (HBV) replication involves the formation of covalently closed circular DNA (cccDNA) and its transcription into pregenomic RNA (pgRNA) in hepatocyte nuclei. The regulatory mechanism of HBV replication by acetyltransferase is thus far not well understood, but human acetyltransferase has been reported as being involved in the regulation of HBV replication. Results: Depletion of KAT8 or HAT1 via RNA interference (RNAi) markedly down-regulated HBV-DNA and pgRNA levels in HepG2.2.15 cells, with KAT8 knockdown reducing both HBsAg and HBeAg more than HAT1 knockdown. Con-sistent with these observations, HBV replication regulators hepatocyte nuclear factor-4-α (HNF4α) and peroxisome proliferator-activated receptor gamma coactivator- (PPARGC-) 1-α were decreased following knockdown of HAT1 or KAT8. Conclusions: These data suggest that KAT8 or HAT1 regulate HBV replication and may be potential drug targets of anti-HBV therapy

Possible Pathway(s) of Metyrapone Egress from the Active Site of Cytochrome P450 3A4: A Molecular Dynamics Simulation

ABSTRACT: To identify a possible pathway(s) for metyrapone egress from the active site of P450 3A4, a 5-ns conventional molecular dynamics simulation followed by steered molecular dynamics simulations was performed on the complex with metyrapone. The steered molecular dynamics simulations showed that metyrapone egress via channel 1, threading through the B-C loop, only required a relatively small rupture force and small displacement of residues, whereas egress via the third channel, between helix I and helices F and G, required a relatively large force and perturbation of helices I, B, and C. The conventional dynamics simulation indicated that channel 2, located between the ␤1 sheet, B-B loop, and F-G region, is closed because of the movement of residues in the mouth of this channel. The findings suggest that channel 1 can be used for metyrapone egress, whereas both channel 2 and channel 3 have a low probability of serving as an exit channel for metyrapone. In addition, residues F108 and I120 appear to act as two gatekeepers to prevent the inhibitor from leaving the active site. These results are in agreement with previous site-directed mutagenesis experiments

Ectopic tissue engineered ligament with silk collagen scaffold for ACL regeneration: A preliminary study

Anterior cruciate ligament (ACL) reconstruction remains a formidable clinical challenge because of the lack of vascularization and adequate cell numbers in the joint cavity. In this study, we developed a novel strategy to mimic the early stage of repair in vivo, which recapitulated extra-articular inflammatory response to facilitate the early ingrowth of blood vessels and cells. A vascularized ectopic tissue engineered ligament (ETEL) with silk collagen scaffold was developed and then transferred to reconstruct the ACL in rabbits without interruption of perfusion. At 2 weeks after ACL reconstruction, more well-perfused cells and vessels were found in the regenerated ACL with ETEL, which decreased dramatically at the 4 and 12 week time points with collagen deposition and maturation. ACL treated with ETEL exhibited more mature ligament structure and enhanced ligament-bone healing post-reconstructive surgery at 4 and 12 weeks, as compared with the control group. In addition, the ETEL group was demonstrated to have higher modulus and stiffness than the control group significantly at 12 weeks post-reconstructive surgery. In conclusion, our results demonstrated that the ETEL can provide sufficient vascularity and cellularity during the early stages of healing, and subsequently promote ACL regeneration and ligament-bone healing, suggesting its clinic use as a promising therapeutic modality. Statement of Significance Early inflammatory cell infiltration, tissue and vessels ingrowth were significantly higher in the extra articular implanted scaffolds than theses in the joint cavity. By mimicking the early stages of wound repair, which provided extra-articular inflammatory stimulation to facilitate the early ingrowth of blood vessels and cells, a vascularized ectopic tissue engineered ligament (ETEL) with silk collagen scaffold was constructed by subcutaneous implantation for 2 weeks. The fully vascularized TE ligament was then transferred to rebuild ACL without blood perfusion interruption, and was demonstrated to exhibit improved ACL regeneration, bone tunnel healing and mechanical properties. (C) 2017 Published by Elsevier Ltd on behalf of Acta Materialia Inc

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

CysB Is a Key Regulator of the Antifungal Activity of <i>Burkholderia pyrrocinia</i> JK-SH007

Burkholderia pyrrocinia JK-SH007 can effectively control poplar canker caused by pathogenic fungi. Its antifungal mechanism remains to be explored. Here, we characterized the functional role of CysB in B. pyrrocinia JK-SH007. This protein was shown to be responsible for the synthesis of cysteine and the siderophore ornibactin, as well as the antifungal activity of B. pyrrocinia JK-SH007. We found that deletion of the cysB gene reduced the antifungal activity and production of the siderophore ornibactin in B. pyrrocinia JK-SH007. However, supplementation with cysteine largely restored these two abilities in the mutant. Further global transcriptome analysis demonstrated that the amino acid metabolic pathway was significantly affected and that some sRNAs were significantly upregulated and targeted the iron–sulfur metabolic pathway by TargetRNA2 prediction. Therefore, we suggest that, in B. pyrrocinia JK-SH007, CysB can regulate the expression of genes related to Fe–S clusters in the iron–sulfur metabolic pathway to affect the antifungal activity of B. pyrrocinia JK-SH007. These findings provide new insights into the various biological functions regulated by CysB in B. pyrrocinia JK-SH007 and the relationship between iron–sulfur metabolic pathways and fungal inhibitory substances. Additionally, they lay the foundation for further investigation of the main antagonistic substances of B. pyrrocinia JK-SH007

CIA-SSD: Confident IoU-Aware Single-Stage Object Detector From Point Cloud

Existing single-stage detectors for locating objects in point clouds often treat object localization and category classification as separate tasks, so the localization accuracy and classification confidence may not well align. To address this issue, we present a new single-stage detector named the Confident IoU-Aware Single-Stage object Detector (CIA-SSD). First, we design the lightweight Spatial-Semantic Feature Aggregation module to adaptively fuse high-level abstract semantic features and low-level spatial features for accurate predictions of bounding boxes and classification confidence. Also, the predicted confidence is further rectified with our designed IoU-aware confidence rectification module to make the confidence more consistent with the localization accuracy. Based on the rectified confidence, we further formulate the Distance-variant IoU-weighted NMS to obtain smoother regressions and avoid redundant predictions. We experiment CIA-SSD on 3D car detection in the KITTI test set and show that it attains top performance in terms of the official ranking metric (moderate AP 80.28%) and above 32 FPS inference speed, outperforming all prior single-stage detectors. The code is available at https://github.com/Vegeta2020/CIA-SSD

Layered double hydroxides as thermal stabilizers for Poly(vinyl chloride): A review

International audiencePoly(vinyl chloride) (PVC), an important thermoplastic polymer widely-used in various fields, requires the use of thermal stabilizers to enhance its thermal stability during polymer processing and practical applications because of the poor thermal stability. Layered double hydroxides (LDHs), two-dimensional anionic layered and versatile filler, are widely considered to be one kind of high-efficient and environment-friendly PVC thermal stabilizers. Interestingly, it is expected to gradually replace the traditional toxic thermal stabilizers such as lead salts. The recent development of LDH thermal stabilizers in PVC resins is here reviewed from four relevant aspects:the thermal stabilization mechanism provided by LDHs,-the chemical composition of metal layers and-of interlayer guests, and-the dispersion state of LDH in PVC composites. The review provides a current picture to help in the choice of manufacturing of high-performance LDH thermal stabilizers